Population Dynamics of Underdominance Gene Drive Systems in Continuous Space

Champer, Jackson; Zhao, Joanna; Champer, Samuel E; Liu, Jingxian; Messer, Philipp W.

doi:10.1021/acssynbio.9b00452

Cited by 52 publications

(136 citation statements)

References 64 publications

Supporting

Mentioning

127

Contrasting

Order By: Relevance

“…Threshold is an indirect measure for the degree of confinement. Zero-threshold drives will potentially spread globally, low and medium levels of confinement will constitute regional drives (possibly local for larger fitness costs), and high threshold systems should remain in a local area, if they are able to successfully persist 34 . **A 2-Locus 2-Toxin-antitoxin (2L2T) underdominance design with two TARE-like alleles.…”

Section: Discussionmentioning

confidence: 99%

Performance analysis of novel toxin-antidote CRISPR gene drive systems

Champer

Kim

Clark

et al. 2019

Preprint

Self Cite

117

View full text Add to dashboard Cite

Gene drives can potentially fixate in a population by biasing inheritance in their favor, opening up a variety of potential applications in areas such as disease-vector control and conservation. CRISPR homing gene drives have shown much promise for providing an effective drive mechanism, but they typically suffer from the rapid formation of resistance alleles. Even if the problem of resistance can be overcome, the utility of such drives would still be limited by their tendency to spread into all areas of a population. To provide additional options for gene drive applications that are substantially less prone to the formation of resistance alleles and could potentially remain confined to a target area, we developed several designs for CRISPR-based gene drives utilizing toxin-antidote (TA) principles. These drives target and disrupt an essential gene with the drive providing rescue. Here, we assess the performance of several types of TA gene drive systems using modeling and individual-based simulations. We show that Toxin-Antidote Recessive Embryo (TARE) drive should allow for the design of robust, regionally confined, population modification strategies with high flexibility in choosing drive promoters and recessive lethal targets. Toxin-Antidote Dominant Embryo (TADE) drive requires a haplolethal target gene and a germline-restricted promoter but should enable the design of both faster regional population modification drives and even regionally-confined population suppression drives. Toxin-antidote dominant sperm (TADS) drive can be used for population modification or suppression. It spreads nearly as quickly as a homing drive and can flexibly use a variety of promoters, but unlike the other TA systems, it is not regionally confined and requires highly specific target genes. Overall, our results suggest that CRISPR-based TA gene drives provide promising candidates for further development in a variety of organisms and may allow for flexible ecological engineering strategies. METHODSDeterministic model. To analyze the dynamics of TA systems, we developed a deterministic, discrete-generation modeling approach. These models were used to demonstrate frequency trajectories and to calculate parameters such as introduction thresholds. Initially, drive/wild-type heterozygotes are added to a population of wild-type individuals at a specified introduction frequency. In each generation, frequencies were tracked for each genotype. Females select a mate randomly, with each male's chance of being selected being proportional to his fitness value. Females then generate a number of potential offspring equal to twice their fitness value.

show abstract

Section: Discussionmentioning

confidence: 99%

Performance analysis of novel toxin-antidote CRISPR gene drive systems

Champer

Kim

Clark

et al. 2019

Preprint

Self Cite

117

View full text Add to dashboard Cite

show abstract

“…We first propose a system that comprises two TARE drive alleles that occupy the same genetic locus ( Figure 1A). A similar RNAi-based system has an invasion threshold frequency of 67% 22,23,25,30,46 . Each of the two drives targets an essential but haplosufficient gene.…”

Section: Design and Analysis Of Underdominance Ta Systemsmentioning

confidence: 99%

“…We next propose a set of drives that comprise TARE, TADE, and TADDE alleles at two genetic loci, with each locus containing a different drive allele (thus allowing any or all the drives to be same-site). Such a system based on RNAi elements has already been well-studied, with an invasion threshold of 27% in the absence of fitness costs 22,23,25,27,28,30,33,46 . As in the 1-locus 2-drive system, each drive allele targets the gene for which the other provides rescue (Figure 2A).…”

Section: Design and Analysis Of Underdominance Ta Systemsmentioning

confidence: 99%

“…Examples of such drives include the Medea toxin-antidote (TA) system 16 , variations thereof 17 , Wolbachia TA elements 18 , reciprocal chromosomal translocations 19 , and a single locus underdominance TA system called RPM-Drive 20,21 . These [22][23][24][25][26][27][28][29][30][31][32][33][34] and other [35][36][37][38][39][40][41] TA designs have been modeled computationally. Yet both demonstrated and proposed systems have proven difficult to successfully engineer in species of interest due to the need for highly specific targets, promoters and RNAi elements, methods that tend to introduce high fitness costs, and other factors.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Design and analysis of CRISPR-based underdominance toxin-antidote gene drives

Champer

Kim

Clark

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

CRISPR gene drive systems offer a mechanism for transmitting a desirable transgene throughout a population for purposes ranging from vector-borne disease control to invasive species suppression. In this simulation study, we assess the performance of several CRISPR-based underdominance gene drive constructs employing toxin-antidote principles. These drives disrupt the wild-type version of an essential gene using a CRISPR nuclease (the toxin) while simultaneously carrying a recoded version of the gene (the antidote). Drives of this nature allow for releases that could be potentially confined to a desired geographic location. This is because such drives have a nonzero invasion threshold frequency, referring to the critical frequency required for the drive to spread through the population. We model drives which target essential genes that are either haplosufficient or haplolethal, using nuclease promoters with expression restricted to the germline, promoters that additionally result in cleavage activity in the early embryo from maternal deposition, and promoters that have ubiquitous somatic expression. We also study several possible drive architectures, considering both "samesite" and "distant-site" systems, as well as several reciprocally targeting drives. Together, these drive variants provide a wide range of invasion threshold frequencies and options for both population modification and suppression. Our results suggest that CRISPR toxin-antidote underdominance drive systems could allow for the design of highly flexible and potentially confinable gene drive strategies.

show abstract

“…as it would alter the number of transgenic versus wild-type individuals that move across population boundaries (Barton, 1979b;Champer, Zhao, et al, 2018;Sudweeks et al, 2019). Differences between populations in size and density also play an important role (Barton, 1979a(Barton, ,1979bBarton & Rouhani, 1991;Barton & Turelli, 2011;Lande, 1985).…”

Section: Discussionmentioning

confidence: 99%

Tethered homing gene drives: A new design for spatially restricted population replacement and suppression

Dhole

Lloyd

Gould

2019

Evolutionary Applications

View full text Add to dashboard Cite

Optimism regarding potential epidemiological and conservation applications of modern gene drives is tempered by concern about the possibility of unintended spread of engineered organisms beyond the target population. In response, several novel gene drive approaches have been proposed that can, under certain conditions, locally alter characteristics of a population. One challenge for these gene drives is the difficulty of achieving high levels of localized population suppression without very large releases in the face of gene flow. We present a new gene drive system, tethered homing (TH), with improved capacity for both localization and population suppression. The TH drive is based on driving a payload gene using a homing construct that is anchored to a spatially restricted gene drive. We use a proof‐of‐concept mathematical model to show the dynamics of a TH drive that uses engineered underdominance as an anchor. This system is composed of a split homing drive and a two‐locus engineered underdominance drive linked to one part of the split drive (the Cas endonuclease). We use simple population genetic simulations to show that the tethered homing technique can offer improved localized spread of costly transgenic payload genes. Additionally, the TH system offers the ability to gradually adjust the genetic load in a population after the initial alteration, with minimal additional release effort. We discuss potential solutions for improving localization and the feasibility of creating TH drive systems. Further research with models that include additional biological details will be needed to better understand how TH drives would behave in natural populations, but the preliminary results shown here suggest that tethered homing drives can be a useful addition to the repertoire of localized gene drives.

show abstract

Population Dynamics of Underdominance Gene Drive Systems in Continuous Space

Cited by 52 publications

References 64 publications

Performance analysis of novel toxin-antidote CRISPR gene drive systems

Performance analysis of novel toxin-antidote CRISPR gene drive systems

Design and analysis of CRISPR-based underdominance toxin-antidote gene drives

Tethered homing gene drives: A new design for spatially restricted population replacement and suppression

Contact Info

Product

Resources

About